Drug eluting composite

ABSTRACT

The present invention relates to materials having therapeutic compositions releasably contained within the materials. The materials are configured to release therapeutic compositions at a desired rate. The present invention also relates to devices incorporating the materials.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending U.S.application Ser. No. 13/103,885 filed May 9, 2011, which is acontinuation-in-part application of U.S. Pat. No. 9,320,890, filed Nov.8, 2010, which is a continuation-in-part application of U.S. applicationSer. No. 12/909,609, filed Oct. 21, 2010 and claims priority to U.S.Provisional Application No. 61/259,491, filed Nov. 9, 2009.

FIELD OF THE INVENTION

The present invention relates to medical devices and materials capableof releasing a therapeutic agent.

SUMMARY OF THE INVENTION

The present invention relates to materials capable of releasing atherapeutic agent contained within the invention at determinedconcentrations over determined periods of time. Pathways are presentwithin the material of the invention for therapeutic agents to traverse.The pathways extend or alter the distance therapeutic agents containedwithin the invention must travel to exit the invention. The time takenfor therapeutic agents to exit the invention is also extended oraffected by the pathways. Pathways are established in the presentinvention with combinations of permeable and impermeable compositionsand/or structures located within the material containing the therapeuticagents. Compositions and/or structures impermeable to a selectedtherapeutic agent are also used as barriers to the therapeutic agent onat least portions of one or more surfaces of the invention. As a result,the therapeutic agent can only exit the invention in areas not covered,contacted, or otherwise constructed with compositions and/or structuresimpermeable to the selected therapeutic agent. Openings are alsoprovided in the compositions and/or structures impermeable to a selectedtherapeutic agent in some embodiments of the invention.

In alternative embodiments, pathways are established in the presentinvention with combinations of permeable and semi-impermeablecompositions and/or structures located within the material containingthe therapeutic agents. Semi-impermeable compositions and/or structuresserve as barriers or other impediments to movement of therapeutic agentsthrough the invention. As a result, the therapeutic agent will pass moreslowly through the semi-impermeable compositions and/or structures thanthrough the permeable compositions and/or structures.

Embodiments of the present invention allow for the tailored delivery oftherapeutic compositions. In some embodiments such tailoring may beeffected by altering the dimensions, compositions, characteristics, andplacement of the impermeable or semi-impermeable compositions and/orstructures without altering the starting amount or distribution oftherapeutic agent present in the embodiment. Embodiments of the presentinvention can be used alone or in combination with other embodiments ofthe invention. The invention can also be a component of a device such ascardiac pacing devices, cardiac defibrillation devices, neurostimulationdevices, endoprostheses such as stents, grafts and stent-grafts,patches, drug delivery devices, such as oral or transdermal deliverypatches and venous or arterial wraps, interventional devices such ascatheters and filters, thrombectomy devices, diagnostic devices such astransducers, sensors, and other medical devices placed in proximity toliving tissue and/or fluids targeted by one or more therapeutic agents.Embodiments of the present invention may be used in combination withmedical devices placed within or on the body for short or long periodsof time.

Implantable embodiments of the invention can be used to elute an antithrombogenic drug into a specific location within the body such as tothe left atrial appendage or other vascular site. Prevention of bloodclots in the region of the left atrial appendage could obviate the needfor a left atrial appendage occluder. In this embodiment, thetherapeutic composition, agent, or compound in the present inventioncould be incorporated into an implantable embodiment and elute a highconcentration of therapeutic when implanted which is subsequentlyrapidly diluted when the blood is washed out into the heart andcirculatory system.

Such implantable embodiments of the present invention can also beconstructed to elute therapeutics over more extended periods of time.

Accordingly, one embodiment of the present invention relates to atherapeutic-releasing material comprising a first biocompatiblepolymeric material having at least one surface and a therapeutic agentreleasably incorporated in at least a portion thereof, wherein a portionof said first biocompatible polymeric material is impermeable to saidtherapeutic agent, and a second biocompatible polymeric materialimpermeable to said therapeutic agent covering substantially all said atleast one surface.

Another embodiment of the present invention relates to atherapeutic-releasing material comprising a porous biocompatiblepolymeric material having at least one surface, a therapeutic agentreleasably admixed with a biocompatible fluoropolymeric copolymer andincorporated in pores of said porous biocompatible polymeric material,wherein a portion of said porous biocompatible polymeric material isimpermeable to said therapeutic agent, and a non-porous biocompatiblepolymeric material impermeable to said therapeutic agent coveringsubstantially all said at least one surface.

A further embodiment of the present invention relates to a firstbiocompatible polymeric material in the form of a film having at leastone surface and a therapeutic agent releasably incorporated in at leasta portion of said film, wherein a portion of said first biocompatiblepolymeric material is impermeable to said therapeutic agent, and asecond biocompatible polymeric material impermeable to said therapeuticagent covering substantially all said at least one surface of said film.

Other embodiments of the present invention relate to medical deviceshaving a therapeutic-releasing material incorporated therein. Forexample, one embodiment relates to a cardiac pacing or IntracardiacCardioverter Defibrillation (ICD) leads comprising a cardiac leadelement having a proximal end and a distal end, an electricallyconductive connector at said proximal end, an electrode located at saiddistal end, at least one electrically conductive element connecting saidconnector to said electrode, and at least a portion of said cardiacelement covered with a therapeutic-releasing material having a firstbiocompatible polymeric material having at least one surface and atherapeutic agent releasably incorporated in at least a portion thereof,wherein a portion of said first biocompatible polymeric material isimpermeable to said therapeutic agent and a second biocompatiblepolymeric material impermeable to said therapeutic agent coveringsubstantially all said at least one surface.

Another embodiment relates to an electrically conductive lead comprisinga lead element having a proximal end and a distal end, an electricallyconductive connector at said proximal end, an electrode located at saiddistal end, at least one electrically conductive element connecting saidconnector to said electrode, a tubular lead tip located at said distalend, and at least a portion of said lead element covered with atherapeutic-releasing material having a first biocompatible polymericmaterial having at least one surface and a therapeutic agent releasablyincorporated in at least a portion thereof, wherein a portion of saidfirst biocompatible polymeric material is impermeable to saidtherapeutic agent and a second biocompatible polymeric materialimpermeable to said therapeutic agent covering substantially all said atleast one surface.

In each embodiment of the present invention, at least one opening can beplaced in the impermeable materials and/or impermeable portions of theinvention to provide a path for therapeutic agents to be released from,or otherwise travel through, the material.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a perspective view of an embodiment the presentinvention.

FIG. 1A illustrates a transverse cross section taken at line “C” in FIG.1.

FIG. 2 illustrates a perspective view of another embodiment of thepresent invention.

FIG. 2A illustrates a transverse cross section taken at line “D” in FIG.2.

FIG. 3 illustrates a perspective view of the embodiment of FIG. 2.

FIG. 4 is a graph.

FIG. 5 illustrates an embodiment of the present invention.

FIG. 6 illustrates a means for delivery or retrieval of the invention.

FIG. 7 illustrates an embodiment of the present invention.

FIG. 8A illustrates an embodiment of the present invention.

FIG. 8B illustrates a transverse cross section taken at the line “A” inFIG. 8A.

FIG. 9A illustrates an embodiment of the present invention.

FIG. 9B illustrates a transverse cross section taken at the line “B” inFIG. 9A.

FIG. 10 illustrates an embodiment of the present invention.

FIG. 11 illustrates an embodiment of the present invention.

FIG. 12 illustrates an embodiment of the present invention.

FIG. 13 illustrates an embodiment of the present invention.

FIGS. 14A-14J illustrate constructions having various barrierconfigurations in accordance with exemplary embodiments of the presentinvention.

FIGS. 15A-15B illustrate embodiments comprising helically wrappedconstructions.

FIG. 16 illustrates embodiments comprising stacked or layeredconstructions.

FIGS. 17A-17G illustrate exemplary constructions comprising gates andexemplary manners for opening gates.

FIG. 18 illustrates a flow chart of an exemplary method of the presentinvention.

FIG. 19A illustrates simple geometry constructs for validating anexemplary CFD analysis.

FIGS. 19B and 19C are plots depicting analytical and CFD elution ratesrespectively for the geometry constructs shown in FIG. 19A.

FIG. 20 illustrates a construction in accordance with an exemplaryembodiment of the present invention.

FIGS. 21A-21D are plots depicting elution rates for the constructions inFIGS. 14A-14J compared to the construction in FIG. 20.

FIGS. 22A-22J depict therapeutic agent concentration over T=2.5 days forthe constructions in FIGS. 14A-14J.

FIGS. 23A-23I depict therapeutic agent concentration over T=20 days forthe constructions in FIGS. 14A-14I.

FIGS. 24A-24C are longer term plots depicting elution rates for theconstructions in FIGS. 14A-14I compared to the construction in FIG. 20.

FIG. 25A illustrates an embodiment of the present invention.

FIG. 25B is a plot comparing elution rates for the constructions in FIG.20 and in FIG. 25A.

FIG. 26 is a plot depicting elution rates for the left hand side of theconstruction in FIG. 17A with that in FIG. 25A.

FIGS. 27A and 27B depict therapeutic agent concentrations at T=22.5hours for FIGS. 25A and 17A, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to materials having therapeuticcompositions releasably contained within the materials. The materialsare configured to release therapeutic compositions at a desired rate.The present invention also relates to devices incorporating thematerials. In preferred embodiments, materials and/or constructions bar,or otherwise impede, movement of therapeutic compositions present withinthe material of the invention. Some embodiments have materials and/orconstructions reducing, or otherwise limiting, the rate of release oftherapeutic compositions from the invention, but not barring, blocking,or otherwise impeding movement of a therapeutic composition through theinvention.

The rate at which therapeutic agents are released from the invention isinfluenced by several factors. These include the chemical composition ofthe components of the invention, the physical relationship of thecomponents, the overall shape of the invention, and any openingsprovided in the invention. The chemical composition of the components ofthe invention include formulations of the therapeutic agent andmaterials containing the therapeutic agent, such as mass fractions,presence or absence of expedients, and the magnitude of the diffusioncoefficient for the invention.

Combinations of compositions and/or structures permeable to therapeuticagents and compositions and/or structures impermeable to therapeuticagents are used in the present invention to establish a pathway alongwhich therapeutic agents move as the agents move through and out of theinvention. As a result, therapeutic agents are preferentially eluted, orotherwise released, from permeable portions of the material and notimpermeable portions. In some embodiments semi-permeable compositionsand/or structures can be used as partial barriers or other partialimpediments to movement of therapeutic compositions through theinvention.

A notable advantage of the invention is the ability to control therelease rate concurrently with the total percentage of therapeuticcompositions released. Some therapeutic compositions are unstable and itis not desirable to leave large or even small portions of thecompositions remaining within the invention for periods of time. Withmore traditional approaches, the rate of release is controlled throughthe mixture of the therapeutic compositions and a polymer.Unfortunately, this can be problematic for systems in which long termrelease is desired with little or no remaining drug left behind. Longperiods of release often mean using high polymer mass fractions relativeto the drug in order to create a low drug diffusion coefficient. Suchsystems inherently entrap portions of the drug that remain within thedrug delivery system permanently or longer than desired. What is neededis a system with low polymer mass fractions (and conversely highdiffusion coefficients) that release drug over a long period with littledrug retention. High diffusion coefficients for small molecules arearound 10⁻⁴ to 10⁻⁸ cm²/sec, with a medium range of 10⁻⁸ to 10⁻⁸cm²/sec, and at the low end at below 10⁻⁹ cm²/sec. These ranges maytrend downward as molecular weight of molecules increases substantially.Unlike the present invention, therapeutic compositions can remain withina conventional device permanently or for undesirable periods of time.

In addition, the invention has a variety of configurations which caninfluence the rate at which therapeutic agents are released from theinvention. The configurations include films, sheets, rods, tubularshapes having luminal spaces, hollow or solid spherical shapes,laminates, wraps, and other shapes.

The material of the present invention includes therapeutic compositions,agents, drugs, or compounds, including but not limited to: smallmolecule drugs; large molecule drugs; medicaments; cardiovascularagents; chemotherapeutics; antimicrobials; antibiotics (e.g.,dactinomycin (actinomycin O) daunorubicin, doxorubicin, and idarubicin),anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) andmitomycin); anesthetics; alkaloids (nicotine); hemostatics;antihistamines; antitumor agents; antilipids; antifungals; antimycotics;antipyretics; antirestenotics (e.g., pimecrolimus, cytochalasin,dicumarol, cyclosporine, latrunculin A, methotrexate, tacrolimus,halofuginone, mycophenolic acid, genistein, batimistat, dexamethasone,cudraflavone, simvastatin, prednisolone, doxorubicin, bromopyruvic acid,cilostazol, carvedilol, mitoxantrone, tranilast, etoposide, hirudin,trapidil, mitomycin C, abciximab, cilostazol, irinotecan, estradiol,diaziquone, dipyridamole, melatonin, colchicine, nifedipine, vitamin E,paclitaxol, diltiazem, vinblastine, verapamil, vincristine, rapamycin(e.g., Albumin-Bound (Nab)-Rapamycin (Abraxane), angiopeptin,everolimus, heat shock proteins, zotarolimus, nitroglycerin,prednisone); antimitotics/antiproliferatives (e.g., including naturalproducts such as vinca alkaloids (e.g., vinblastine, vincristine, andvinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide,teniposide), alkylating agents such as nitrogen mustards(mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC));antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (e.g., estrogen);vasodilators; hypertensive agents; oxygen free radical scavengers;vitamins; antivirals; analgesics; antiinflammatories (e.g.,adrenocortical steroids (cortisol, cortisone, fludrocortisone,prednisone, prednisolone, 6a-methylprednisolone, triamcinolone,betamethasone, and dexamethasone, dexamethasone sodium phosphate,dexamethasone acetate, beclomethasone dipropionate); non-steroidalagents (e.g., salicylic acid derivatives such as aspirin);para-aminophenol derivatives e.g., acetominophen; indole and indeneacetic acids (indomethacin, sulindac, and etodalac), heteroaryl aceticacids (tolmetin, diclofenac, and ketorolac), arylpropionic acids(ibuprofen and derivatives), anthranilic acids (mefenamic acid, andmeclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone,and oxyphenthatrazone), nabumetone; gold compounds (auranofin,aurothioglucose, gold sodium thiomalate); diagnostic agents;visualization agents; angiographic contrast agents; peptides; proteins;antibodies (e.g., britumomab (Zevalin), bevacizumab (Avastin), rituximab(Rituxan), Cetuximab (Erbitux), Ofatumumab (Arzerra), Panitumumab(Vectibix), Trastuzumab (Herceptin), and Tositumomab (Bexxar)); enzymes(e.g., L-asparaginase); antiplatelet agents (such as G(GP)IIbIIIainhibitors and vitronectin receptor antagonists); insulin; phasecontrast agents, and radiopaque agents; thrombolytics intended tofacilitate the breakup of thrombus; anticoagulants (e.g., heparin,synthetic heparin salts and other inhibitors of thrombin), intended toprevent thrombosis; fibrinolytic agents (such as tissue plasminogenactivator, streptokinase and urokinase), aspirin, dipyridamole,ticlopidine, clopidogrel, abciximab; antimigratories; antisecretories(e.g., breveldin); immunosuppressives: (cyclosporine, tacrolimus(FK-S06), sirolimus (rapamycin), azathioprine, mycophenolate mofetil);angiogenic agents: vascular endothelial growth factor (VEGF), fibroblastgrowth factor (FGF); angiotensin receptor blocker; nitric oxide donors;anti-sense oligionucleotides and combinations thereof; cell cycleinhibitors, mTOR inhibitors, and growth factor signal transductionkinase inhibitors; RNA; viruses; and combinations thereof.

In a preferred embodiment of the present invention, a film materialpermeable to a therapeutic compound is impregnated or coated with acopolymer into which has been admixed the therapeutic compound. Thepreferred film material is an expanded polytetrafluoroethylene (ePTFE)construction. The copolymer is preferably atetrafluoroethylene/perfluoroalkylvinylether (TFE/PAVE) copolymer, andmore preferably a tetrafluoroethylene/perfluoromethylvinylether(TFE/PMVE) copolymer, made generally as taught by U.S. Pat. No.7,049,380, and US Publication 20040024448 to Chang et al., bothincorporated by reference herein. The resulting coated film may becomeless-permeable and preferably impermeable to the therapeutic compound.In some instances the permeability of the film may not change.

In some embodiments, a material impermeable to the therapeuticcomposition, agent, or compound is placed on at least one surface of thetherapeutic-containing, coated film material as a “capping layer” toprevent movement of the therapeutic agent or compound through or out ofthe invention at the location of the impermeable material. The materialfor the “capping layer” is preferably formed of a polymer such as asilicone composition. Depending on the embodiment, the capping layermaterial is applied either to a portion of the coated film material orall of the film material. The portion of the coated film material whichis not covered by the capping layer material preferentially elutes thetherapeutic composition, agent, or compound when exposed. The cappinglayer material may be applied over the coated film material after thefilm material is applied to a substrate.

In some embodiments, the impermeable material, be it a “capping-layer”or a coated film has at least one opening therein.

In some embodiments, the present invention is combined with a substratein the form of a device or other construction. In these embodiments, acoated film material is applied to all or a portion of the substrateunderlying the invention. The coated film material may be cut into atape and applied by wrapping the tape around the substrate. The tape iswrapped spirally, helically and/or longitudinally around at least aportion of the substrate. An adhesive may be used as needed to adherethe spirally-wrapped layers of film. If the coated film is “capped” witha capping layer which prevents elution from the coated film construct,the capping layer may also serve as an adhesive. The coated film may beapplied to the substrate with the coated side facing the substrate orfacing away from the substrate. Substrates may include tubes, rods,pellets, or any other three dimensional object, including substrateswhich may be a component of an assembled device. Substrates may be madeof metals, polymers, and the like. The substrate may be shaped oraltered to form elution pathways through and out of the presentinvention.

As used herein, the term “bioabsorbable” refers to a physiologicalprocess in which at least a portion of a material hydrolyzes, degrades,or otherwise dissolves in living tissue or biological fluid.

As used herein, the term “permanent implant” refers to a medical deviceintended to be implanted in a patient for all or most of the life of thepatient.

As used herein, the term “semi-permanent implant” refers to a medicaldevice intended to be implanted in a patient for less than most of theexpected life of the patient. Semi-permanent implants are often accessedfollowing implantation for removal of the device or other procedurerelated to the device.

Referring to FIG. 1, coated film (10) has a therapeutic composition,agent, or compound (not shown) incorporated with a film. Coated film(10) is applied over a substrate (18). A capping layer (12) is appliedover coated film (10). The capping layer (12) is either made ofmaterials impermeable to the particular therapeutic composition, agent,or compound or constructed to be impermeable to the particulartherapeutic composition, agent or compound.

In this embodiment, the substrate (18) is a tubular structure with aluminal space (16). Material of the capping layer (12) covers only aportion of the coated film material (10) thereby leaving a portion ofcoated film material exposed around an edge, or lip, of the substrate(18). The exposed portion of the coated film material (10) has athickness dimension (11).

This embodiment is also illustrated in FIG. 1A as a transverse crosssection taken at line “C” in FIG. 1 showing substrate material (18),luminal space (16), coated film material (10) and capping layer material(12).

In practice, the embodiment illustrated in FIG. 1 is placed in contactwith or in proximity to a bodily tissue or fluid. Once in contact withtissue and/or fluid, the therapeutic composition, agent, or compound(not shown) contained within coated film (10) is preferentially elutedfrom those portions of the coated film material not covered by materialof the capping layer (12). In this embodiment, for example, thetherapeutic composition, agent, or compound elutes or otherwise exitsthe invention from an uncapped, or otherwise uncovered, edge (11)surrounding the opening of luminal space (16). The therapeuticcomposition, agent, or compound in the coated film material (10) maydiffuse, or otherwise migrate, from portions of the coated film material(10) covered by material of the capping layer (12) and exit theinvention from uncovered and exposed areas of the coated film material(10).

Another embodiment of the present invention is illustrated in FIG. 2. Inthis embodiment, coated film material (10) has a therapeuticcomposition, agent, or compound (not shown) incorporated into the film.The coated film material (10) is applied over a substrate (18). Acapping layer material (12) is applied over the entire exterior surfaceof coated film material (10). The capping layer (12) is either made ofmaterials impermeable to the particular therapeutic composition, agent,or compound or constructed to be impermeable to the particulartherapeutic composition, agent, or compound. An opening (13) in the formof a hole is made through substrate 18, exposing coated film material(10) to the luminal space (16) of the substrate (18). A porous materialmay be placed over opening (13) and between the substrate (18) andcoated film material (10). Additionally, this material placed overopening (13) may modulate release of a therapeutic composition, agent,or compound.

FIG. 2A is a transverse cross section taken at line “D” in FIG. 2showing substrate (18), luminal space (16), coated film material (10),capping layer material (12), and opening (13).

In practice, the embodiment illustrated in FIG. 2 is placed in contactwith or in proximity to a tissue or fluid. Once in contact with tissueand/or fluid, the therapeutic composition, agent, or compound in coatedfilm material (10) preferentially elutes through opening (13) and intoluminal space (16) including surrounding fluid and/or tissues (notshown). The therapeutic composition, agent, or compound in coated filmmaterial (10) may migrate to opening (13) from portions of coated filmmaterial (10) covered by capping layer material (12) and located awayfrom opening (13).

FIG. 3 is a perspective view of the embodiment illustrated in FIG. 2except a cover material (17) covers luminal space (16) as shown in FIG.2. Optionally, an opening (20) can be made in cover material (17)through which tissue fixation means (19), such as a screw, may beincluded. Additional means of tissue fixation include appropriateanchors, barbs, hooks or adhesives. The tissue fixation means can bemade of metallic or polymeric materials. The metallic or polymericmaterials can be bioabsorbable or non-bioabsorbable. An example of abioabsorbable metal is magnesium. An example of a bioabsorbable polymeris polyglycolic acid commonly known as PGA.

In practice, the embodiment illustrated in FIG. 3 is anchored intotissue using tissue fixation screw (19) and the therapeutic composition,agent, or compound in coated film material (10) is allowed topreferentially elute from opening (13) into luminal space (16) and outof opening (20) into surrounding tissues and/or fluids. The embodimentillustrated in FIG. 3 may be used for implantation into the heart andother tissues as described below. For example, in cardiac leads a tissuefixation screw (19) is often placed into the septum of the rightventricle.

FIG. 4 is a graph of the cumulative mass of drug released as a functionof time for the embodiment described in Example 1.

FIG. 5 illustrates another embodiment of the present invention. Ahousing (26) includes a therapeutic eluting construction of the presentinvention with a means to attach the housing (26) to tissue such as atissue attachment screw (28). Depending on the application, the housing(26) may be attached to a tissue region or anatomical location such as aleft atrial appendage (30). The attachment may be permanent orsemi-permanent in the event the housing (26) is subsequently removed andoptionally exchanged.

The housing (26) may be incorporated in the embodiment described inExample 1. The housing (26) may be made of metallic or polymericmaterials. The housing (26) is solid, hollow, or includes features suchas perforations (32) as illustrated in FIG. 7.

In one embodiment, both a housing (26) and tissue attachment screw (28)are made of materials which are bioabsorbable. In one embodiment, theentire housing (26) is a solid bioabsorbable material having atherapeutic composition, agent, or compound incorporated therein. Overtime, the entire housing implant will hydrolyze, or otherwise dissolve,while eluting the therapeutic agent. In yet another embodiment, thetherapeutic composition, agent, or compound incorporated within thebioabsorbable material may vary in both composition and concentration.For example, the housing (26) may be constructed such that the initialeluted dosage of therapeutic composition, agent, or compound may be veryhigh, with potency dropping off over time as a function of variablebioabsorption produced by using materials of varying bioabsorbability.In one embodiment, such variable elution may be utilized by constructinga housing (26) with multiple layers of therapeutic-loaded bioabsorbablematerials, each layer having a different therapeutic concentration oreach layer having a different rate of bioabsorbability, or a combinationof both.

Elution rates may also be varied by modifying the housing (26). Forexample, the housing (26) may include perforations (32) as illustratedin FIG. 7. The perforations (32) permit elution from the inner regionsof the housing (26) or increase surface area of the housing (26). In oneembodiment, elution rates may be controlled by overwrapping or encasinga housing (26) within a porous or semi-permeable covering material (34)as illustrated in FIG. 7. A porous expanded polytetrafluoroethylene(ePTFE) material exhibits biocompatibility and substantial chemicalinertness. A porous expanded polytetrafluoroethylene material for theoverwrapping or encasing material is a preferred material.

In some situations, it may be necessary to retrieve or replace animplanted embodiment of the present invention. Retrieval can beaccomplished with a grasping tool. In one embodiment, a magneticattachment is used to retrieve or replace an implanted device (see e.g.,FIG. 6). Magnets (36) may be embedded within or on the surface of thehousing (26) and the associated catheter (38). The magnets (36) areconfigured to exert an attractive force between the magnets. Once asufficient magnetic attraction has been established, in-situ capture andmovement of housing (26) can be performed. A sheath (40) may be used inthe present invention. The sheath (40) is advanced over a housing (26)and the entire system rotated to cause release of the tissue attachmentscrew (28) and removal from the implant site.

Embodiments of the present invention may be configured for a variety ofpurposes, including therapeutic-eluting tips for cardiac pacing orIntracardiac Cardioverter Defibrillation (ICD), or neurostimulationleads; or other therapeutic-eluting devices for placement in proximityto other body tissues. Once placed at the desired location byinterventional or surgical means and enclosed by tissue or affixed totissue with an anchor, the invention can be of therapeutic value bylocally or systemically delivering a drug. Although the left atrialappendage (30) implantation site is described herein, it should beappreciated that the present invention may be applicable to a variety ofother applications, such as in or proximate various organs, e.g., theliver, kidney, brain; or peripheral vascular system. Accordingly, use ofthe present invention need not be constrained to the cardiovascularsystem. For instance, embodiments for implantation within a sinus cavityand loaded with an antihistamine or other allergy-symptom relievingagent are contemplated. Additional embodiments include drug deliverydevices for oral or transdermal implantation or fixation which areloaded with a therapeutic agent, like insulin.

FIG. 8A illustrates an embodiment of the present invention. Referring toFIG. 8A, therapeutic-releasing construction (40) is comprised of abiocompatible material, for example a coated film (10), a “cappinglayer” or impermeable material (12), and an opening (42) extendingthrough impermeable material (12).

Therapeutic-releasing construct (40) may be constructed to be anydimension but could be constructed to have a length of about 2 cm with awidth of about 0.8 cm. The capping layer (12) may be of any thickness. Athickness of about 0.01 mm may be used. While shown as surrounding allof coated film (10), the capping layer (12) may surround only a portionof coated film (10). Coated film (10) may be of any thickness. Athickness of 0.5 mm may be used. Opening (42) may be formed by avoidingcovering a portion of coated film (10) or by cutting through cappinglayer (12) by means as known in the art. Opening (42) may act as adiffusion barrier to further modulate release by providing a cover ofpermeable material over opening. Opening (42) may be of any dimensionand shape. An opening (42) with the shape of a circle and the diameterof about 1 mm may be used. More than one opening may be used. Theopening (42) may be placed at any location through impermeable material(12).

The rate at which therapeutic agents are released fromtherapeutic-releasing construction (40) will vary should the amount ordimensions of coated film (10) be varied, or the size or position ofopening (42) be altered.

It will be understood that instead of using coated film (10) atherapeutic composition, agent, or compound, including one incorporatedin a matrix, for example a polymer, could also be used in embodiments ofthe present invention.

This embodiment is also illustrated in FIG. 8B as a transverse crosssection taken at line “A” in FIG. 8A showing coated film (10) andcapping layer material (12) and opening (42).

In practice, the embodiment illustrated in FIG. 8A-8B is atherapeutic-releasing construction or material (40) that may be appliedto a variety of medical devices or used in vivo for therapeuticcomposition, agent, or compound delivery as discussed previously. Ifapplied to a medical device, placement of the opening (42) may bemanipulated to be in contact with tissue and/or fluid. Once in contactwith tissue and/or fluid, the therapeutic composition, agent, orcompound (not shown) contained within coated film (10) is preferentiallyeluted from those portions of the construction (40) not covered bymaterial of the capping layer (12). In this embodiment, for example, thetherapeutic composition, agent, or compound elutes or otherwise exitsthe invention from the illustrated opening (42). The therapeuticcomposition, agent, or compound in the coated film (10) may diffuse, orotherwise migrate, through portions of the coated film (10) covered bymaterial of the capping layer (12) and exit the invention from uncoveredand exposed areas of the coated film (10).

FIGS. 9A and 9B illustrate an embodiment of the present invention withFIG. 9B being a transverse cross section taken at line “B” in FIG. 9A.Referring to FIGS. 9A and 9B, therapeutic-releasing construction (50) isconstructed as described for the embodiment in FIGS. 8A and 8B with acoated film (10), a “capping layer” or impermeable material (12), and anopening (42) extending through impermeable material (12). A barriermaterial (52) which may be impermeable or semi-permeable to theparticular therapeutic composition, agent, or compound incorporated incoated film (10) is disposed within coated film (10). The height ofbarrier material (52) is shown in FIG. 9B as extending the full verticaldistance between the capping layers (12) but may be dimensioned toextend only a portion of this distance. The length and/or width ofbarrier material (52) may be varied as well, as may the number ofbarriers (52).

In FIG. 9A (with upper capping layer (12) removed for clarity), barriermaterial (52) is shown extending from one edge of the coated film (10)toward a second edge and ending a distance away from said second edge.This distance alone or in combination with the number or dimensions ofbarrier materials (52) may be varied and can be used to tailor thetransport or elution path of therapeutic agents through coated film (10)as is represented by a path of a theoretical molecule as illustrated inFIG. 9a as a dotted line with an arrow indicating the exit at theopening (42). Altering this elution pathway in any way may alter theelution rate of the therapeutic composition, agent, or compound. Elutionpathways may also be altered by varying the orientation of the barriermaterial (52) as further illustrated in FIGS. 10-12.

In practice, the embodiment illustrated in FIG. 9A-9B may be used invivo for therapeutic composition, agent, or compound delivery or appliedto a substrate, for example a medical device as listed above.

FIG. 10 illustrates an embodiment of the present invention wherein thebarrier material (52) has been positioned off the center line oftherapeutic-releasing construction (60) and extending a longitudinaldistance from one edge of coated film (10). Barrier (52) may also beplaced at a location away from said edge. Any orientation of barriermaterial (52) may be employed. A barrier material (52) having anorientation of a non-zero angle off the longitudinal center line couldbe used. An orientation of about five degrees may also be used. Asdescribed previously, any length of barrier material (52) may be used. Alength of barrier material (52) leaving about a 1 mm gap between the endof the barrier material (52) and edge of coated film (10) may also beused.

Depending on the shape, dimensions, and location of barrier materials(52), those portions of coated film (10) separated by barriers (52) mayact as reservoirs for therapeutic compounds admixed or otherwiseincorporated with coated film (10). Generally, the larger the volume ofthe separated portions of coated film (10) the more likely thoseportions are to serve as reservoirs. The smaller the volume the morelikely the portions are to serve more as elution channels. Whenfunctioning as reservoirs, coated film volumes may contain differenttherapeutic compounds. For example in FIG. 10, the portion of coatedfilm (10) above barrier (52) and proximate opening (42) could contain ananti-thrombogenic therapeutic and the lower portion of coated film (10),located below the barrier (52), could contain an anti-inflammatory. Inuse, the therapeutic-releasing construct (60) could be positionedproximate a vascular occlusion with the anti-thrombogenic therapeuticeluting through the nearest opening (42), eluting first to dissolve theocclusion and the anti-inflammatory agent eluting subsequently to lesseninflammation at the site of the lesion.

FIG. 11 illustrates an embodiment of the present invention. FIG. 11shows therapeutic-releasing construction (70) as previously describedbut with barrier materials (52) positioned perpendicular to thelongitudinal center line of construction (70) and closer together thanthose shown in FIGS. 9A and 9B. This embodiment illustrates an elutionpathway having these attributes: This embodiment provides a portion oftherapeutic compound in close proximity to the opening with no barriersfor a burst release followed by a longer release time for the majorityof therapeutic compound contained beyond the barriers (i.e., to theright of the last barrier (52) in FIG. 11). The three barriersillustrated in FIG. 11 greatly extend the pathway for the therapeuticcompound to travel. Moving the barriers closer to the opening willreduce the burst release of therapeutic compound and result in moretherapeutic compound being released later in time. Having the barriersrelatively close together results in a small amount of therapeuticcompound between the barriers effectively creating two reservoirs.Spacing them further apart can create a four reservoir system asillustrated in FIG. 9A.

FIG. 12 illustrates an embodiment of the present invention. FIG. 12shows therapeutic-releasing construction (80) as previously describedbut with barrier materials (52) positioned parallel to the longitudinalcenter line of construction (70) and placed close to one another. Thisembodiment illustrates an elution pathway longer than those shown inFIGS. 9 through 11. In this embodiment, the therapeutic compound isreleased for the longest period of time, relative to the otherconstructions. As previously described, the amount of therapeuticcompound released earlier or later can be tailored by moving thebarriers closer or further away from the hole, respectively. Spacing thebarriers further apart will alter the size of areas of the coated film(10) serving as therapeutic agent reservoirs.

FIG. 13 shows a cross section of therapeutic-releasing construct (90) aspreviously described but barriers (52) have been created by fusing aportion of the opposing capping layers (12) together after removingcoated film (10). This construct may be achieved by using variousmethods known in the art. For example, coated film (10) may be placed onthe capping layer (12) which includes outlet (42). Then desired portionsof the coated film (10) are removed, for example, with a laser. Thencapping layers (12) are added to all edges of therapeutic-releasingconstruct (90) and a capping layer (12) is added to the top of theconstruct, opposite the capping layer (12) with opening (42). Theconstruct (90) is then placed into a die which presses a portion of theopposing capping layers (12) together, fusing them to create animpermeable barrier (52). In addition to pressure, the fusing togetherof portions of the capping layers (12) may be augmented by applicationof heat or adhesives to the areas where coated film (10) has beenpreviously removed. It will be understood that the shape and dimensionsof impermeable barrier (52) can be varied to achieve the desired elutingpathway(s).

Additional embodiments of therapeutic-releasing constructions of theinvention are illustrated in FIGS. 14A-14J, each of which may compriseimpermeable material (12), one or more openings (42), and one or morebarriers or barrier materials (52), the latter labeled only once in eachFigure for clarity and simplicity. (Note that FIGS. 14A and 14B aresubstantially similar to FIGS. 9A and 10 respectively.) FIGS. 14A and14C differ in the orientations of barriers (52) to opening (42), withthe longer elution distance of 14A contributing to a slower elutionrate. FIGS. 14A and 14I differ in the size of the gaps between barriers(52) and the edge of impermeable material (12), with the larger gaps of14A resulting in a faster elution rate. The large volume below barrier(52) in FIG. 14B may act as a reservoir, as previously described. Tightconstriction near opening (42) in both FIGS. 14D, 14G, and 14H greatlyreduces the elution rate. Similarly, the small opening (or“constriction” of the elution path) between the three barrier (52) endsclosest to opening (42) in FIG. 14F decreases the elution rate, comparedto that in FIG. 14E. The construction depicted in FIG. 14J showsconstructions may have more than one opening (42), in this case two.

Importantly, the illustrated embodiments should not be construed aslimiting, but rather examples of constructions which regulate elutionrates and thus can be tailored for a wide range of drug deliveryapplications. Generally speaking, the present invention comprisestherapeutic-releasing constructions having one or a plurality oftherapeutic agent elution pathways defined by impermeable orsemi-permeable materials, compositions, structures and/or barriers. Inexemplary embodiments, impermeable or semi-permeable materials,compositions, structures and/or barriers provide for the manipulation ofan elution rate without necessarily altering the base geometry ordimensions of the construction or altering the amount or type oftherapeutic agent or altering the composition or dimensions of a coatingor matrix in which a therapeutic agent may be carried.

Both relatively simple, as well as more complex, elution pathways havingprimarily x and y directional components (the z direction beingsignificantly smaller than the x and y directional components) arecontemplated herein, such as those illustrated. To name just a few, theproximity of the distance between barriers to the opening, the distancebetween barriers, the gaps between barrier ends and impermeable materialedges or top/bottom/side walls, volume between barriers, constrictionbetween barriers, staggering of barriers, orientation of barriers,dimensions of barriers, composition of barriers, permeability ofbarriers (should they be semi-permeable), shape of barriers, e.g., abarrier need not be straight as shown in the Figures but may be rounded,contoured, segmented and the like), and tortuosity can be adjusted toalter the elution rate. Tortuosity may be defined as the variabilityfrom a straight line of an elution pathway as affected by one or morewell-placed impermeable or semi-permeable materials, compositions,structures and/or barriers. In addition, barriers need not be attachedto or placed against adjacent impermeable materials but instead may beplaced in the middle of a construction with elution occurring betweenthe barrier ends and nearby impermeable material side walls, forexample.

Additionally, a plurality of therapeutic-releasing constructions may bearranged such that one or more elution pathways extend in the zdirection. In exemplary embodiments, one or more constructions arewrapped about or otherwise bonded or adhered to the interior and/orexterior of an implantable device to extend an elution pathway in the zdirection, which may lengthen the diffusion length. A construction maybe wrapped about or otherwise bonded or adhered to an implantable devicein any number of configurations, for example, helically, sinusoidally,in a zig-zag configuration, a ladder configuration, etc.

Constructions need not be limited in their z-direction or thickness.Thicker coatings of drugs and/or matrices, along with higher barriers(in the z-axis) are also contemplated. Although not limited to suchthicker constructs, barriers may be made to extend only partiallybetween a lower and upper impermeable material. This in turn could beused to further tailor elution pathways in the z-axis.

Additionally, constructions of the present invention may be made tofunction themselves as medical devices. For example a flat or semi-flatconstruction of the invention may be surgically or percutaneously placedadjacent a tissue region into which one or more therapeutics aredelivered in a tailored, controlled fashion. A flat construct maysimilarly be wrapped upon itself in a spiral and placed in the body foranother form of controlled therapeutic agent elution.

In another embodiment, and with reference to FIG. 15A, a construction ishelically wrapped about an implantable device to create a helical path,which may lengthen the diffusion length. This embodiment shows atherapeutic agent loaded strip (56) in a helix orientation attached to asolid impermeable substrate (58) on the inside and fully covered with aimpermeable or semi-impermeable capping layer (62) on the exterior.Strip (56) is preferably porous to a drug or otherwise allows it totravel within strip (56). Capping layer (62) may comprise a polymer. Inthis configuration, the therapeutic agent must follow the helical pathin the direction of the arrows to reach an elution opening (64) wherethe therapeutic agent can then elute into the inner diameter of solidimpermeable substrate (58). In exemplary embodiments, changing the widthof therapeutic agent loaded porous polymer strip (56) and the pitch ofthe pattern (helix) can be used to alter the total therapeutic agentloading, elution pathway, and therapeutic agent elution rate. In suchembodiments, the spacing between therapeutic agent loaded porous polymerstrip (56) can be created with a laser ablation or a die cuttingprocess. Capping layer (62) may be attached over the full length oftherapeutic agent loaded porous polymer strip (56) and solid impermeablesubstrate (58). In yet other embodiments, polymer non-porous cappinglayer (62) is attached over less than the full length. Optionally,porous polymer strip may contain barriers as previously described.

In another embodiment, and with reference to FIG. 15B which is a crosssection A-A of FIG. 15A, rather than employing a laser ablation or diecutting process, polymer non-porous capping layer (62) can be bonded oradhered to solid impermeable substrate (58) with gaps (66) forming ahelical barrier which will direct flow of the therapeutic agent elutionthrough a helical pattern that is therapeutic agent loaded porouspolymer strip (56) and thereby allow the agent to directly flow toelution opening (64) into the inner diameter of solid impermeablesubstrate (58) in the direction of the arrows.

In yet other embodiments, a plurality of constructions may be stacked inproximity to each other, for example, to deliver a plurality oftherapeutic agents, or the same therapeutic agent but in differentpotencies (i.e., using different concentrations). In the embodimentshown in FIG. 16, construction cylinders (68), (72), (74), and (76) arestacked inside one another and contain therapeutic agents (78), (82),(84), and (86) respectively, and have elution pathways exiting atopenings (88), (92), (94), and (96) respectively. This configurationprovides for timed, mostly sequential elution of a plurality oftherapeutic agents, or the same therapeutic agent but in differentpotencies, for example. Additionally, construction cylinders (68), (72),(74), and (76) may be rotated to align or offset openings (88), (92),(94), and (96) and thus alter the elution rate. Optionally, cylinders(68), (72), (74), and (76) may be formed as cups or enclosed on bothopen ends to form enclosed cylinders.

Optionally, the cylinders may contain barriers as previously described.For example, the cylinders may be formed by bending the construction inFIG. 9A into a cylinder.

A therapeutic-releasing construction may comprise one or more gatesinterjected in or otherwise creating a barrier to an elution pathwaywhich are openable or may open and close. FIG. 17A, for example,illustrates a construction having impermeable material (12), opening(42), barrier material (52), and a gate (98). In this embodiment, aninitial burst delivery of a therapeutic agent located in the volume onthe left of gate (98) is followed by a slower delivery of a therapeuticagent contained in the volume and between the barriers (52) to the rightof gate (98). Optionally, the therapeutic agents (or agent carriers) oneach side of gate (98) may differ in type or concentration. Thus, one ormore gates in an exemplary embodiment provides for a plurality ofelution profiles which are, at least in part, controlled by actuation ofa gate. In a preferred embodiment, a gate provides a reservoir fordelivery of a therapeutic agent according to a different elution profileor for delivery at a later time. Gates may also be opened in a stagedmanner, for example, where an initial actuation allows release andsubsequent actuations allow release of alternate therapeutic agents.

A plurality of elution pathways defined within a single construction, asdescribed herein, may be useful in several respects, for example, toenable the delivery of a single therapeutic composition according todifferent elution rates, or to enable the delivery of multipletherapeutic compositions (or different potencies of a single therapeuticcomposition) according to the same or different elution rates. Gatesimpeding pathways of therapeutic-releasing construction may be opened invarious manners, including but not limited to a mechanical or electricaldevice, including inductive devices, by a bioabsorbable portion,mechanically, e.g., upon pressure applied to the body proximate theconstruction, by a weakened portion, or remotely (e.g., by transfer ofenergy such as magnetic and ultrasound energy, etc.). If constructionsare used in association with electrically-powered devices, e.g., cardiacleads, gates may also be opened by application of electrical energyselectively shunted from the electrical device. Referring to FIG. 17A,in another embodiment, the top and bottom sides of the construction maybe pinched together to close off gate (98) with a subsequent release ofsuch pinching resulting in the return of top and bottom sides to theiroriginal position and the reopening of gate (98).

FIG. 17B illustrates an embodiment comprising a bioabsorbable ordissolving plug (102) occluding a gap between impermeable material (104)and thereby preventing elution of a therapeutic agent (106). Asabsorbable plug (102) decays over time, therapeutic agent (106) isreleased. Non permeable but absorbable or dissolvable plugs may befabricated from absorbable metals such as magnesium or fine grainaustenitic stainless steel. Polymeric bioabsorbable materials suitablefor use include, but are not limited to, poly(DL lactide-co-glycolide)copolymers, polyglycolide, poly(DL lactide), poly(L lactide),polycaprolactone, polydioxanone, and polyhydroxybutyrate and the like.

FIG. 17C illustrates an embodiment comprising a first impermeablematerial (104) and a second impermeable material (108), having holes(105) and (109) respectively completely or partially offset from oneanother, thereby preventing at least some elution of a therapeutic agent(106). First impermeable material (104) and second impermeable material(108) are moved relative to each other thereby aligning holes (105) and(109) and therapeutic agent (106) is released. Actuation may beaccomplished in various manners. In a preferred embodiment, theconstruction is first impermeable material (104) and second impermeablematerial (108) wrapped ePTFE tubes having at least one helically-wrappedlayer. Optionally, if more than one layer is used, the layers may bewrapped on an opposing bias. The first impermeable material (104) mayact as an capping layer through which is placed a hole (105). The secondimpermeable material (108), which may be wrapped in the oppositedirection of the first impermeable material (104), may serve as anothercapping layer also with an opening (109) or series of openings (109) cutin a particular location. When first impermeable material (104) tube andsecond impermeable material (108) tube are slide relative to oneanother, holes (105 and 109) align and therapeutic agent (106) isallowed to elute.

With reference to FIG. 17D, the construction may comprise an impermeablematerial (104) having a weakened zone (112) preventing elution of atherapeutic agent (106). Weakened zone (112) may be compromisedmechanically, for example by a mechanical or electrical device pullingthe weakened zone apart. In another embodiment, weakened zone (112) iscompromised upon radial dilation about weakened zone (112). An exampleof a weakened zone in an ePTFE construct would be a thinned anddensified area. A zone as such can easily be produced with proper heatand pressure using techniques commonly known to those skilled in the artof PTFE processing.

In a similar embodiment, and with reference to FIG. 17E, theconstruction may comprise an impermeable material (104) having aweakened zone (114) preventing elution of a therapeutic agent (106). Inthis embodiment, weakened zone (114) may be compromised remotely (e.g.,by transfer of energy such as magnetic and ultrasound energy, shockwaves, etc.). For example, in various embodiments of the presentinvention, ultrasound energy, as used in extracorporeal shock wavelithotripsy or similar techniques known to persons skilled in the artmay be used to compromise weakened zone (114).

In another embodiment of the invention shown in FIGS. 17F-17G, a drugeluting construction comprises first impermeable material (104) formedas an inner tube which is located within a second impermeable material(108) formed as an outer tube. The assembly may include a lumen 115. Atherapeutic agent 106 is applied to a part of the exterior surface ofthe inner tube. As shown in FIG. 17F, a portion (117) of the exterior ofthe inner tube is not coated with drug. A hole 42 (or holes) is createdthrough the external tube. The hole is located such that in a firststate the uncoated portion of the exterior of the inner tube is exposedthrough the hole. Each tube is constructed by helically wrapping a filmtape around a mandrel. A preferred film material is ePTFE. The film tapewrappings overlap one another (overlaps not shown) but are not attachedat the overlapped regions. Instead, the film wraps are secured at theends of each tube. This allows the wraps to move relative to one anotherwhen a tube is radially torqued. Upon such torquing the tube expands(and may foreshorten). In the tube within a tube construct shown in FIG.17G radial torquing of the two tubes opposite each other will cause bothtubes to expand. At the same time, the wrappings in both tubes willslide radially relative to one another. Doing so changes the relativeangle between the wrap angles on the first and second tubes. In FIG. 17Fangle θ₁ exists in a first, untorqued state and as shown in FIG. 17G alesser angle θ₂ is created when both tubes are radially torqued into asecond, expanded state. This change in relative angle serves to movehole 42 from lying over the portion of the inner tube which is notcoated with a drug to a portion of the inner tube which is coated. This,in turn, allows release of the drug from the construction.

Shape memory materials may also be incorporated to accomplish some ofthe objectives described herein. In addition to gates, barriersthemselves may also be mechanically adjusted in vivo, at the patientbedside or during manufacture. For example, and with momentary referenceback to FIGS. 14G and 14H, circular barriers (52) may be rotated toalign or offset gaps between barriers and thus alter the elution rate.Additionally, in some embodiments, one or more elution pathways lead toa plurality of openings, for example, as illustrated in FIG. 14J.

In sum, elution pathways may be structurally configured in various waysto alter the elution rate of therapeutic compositions from constructionopenings. Depending on the pathway(s), wrapping, stacking, gate(s),barrier mobility, opening(s), etc., elution rates over time may beconfigured to be linear, curved, a polynomial of any degree, acombination thereof, etc. In like manner, elution rates may beconfigured to be continuous or intermittent with a constant or variablefrequency. In preferred embodiments, elution rates are controlledwithout altering the base geometry or dimensions of the construction oraltering the therapeutic agent.

Exemplary embodiments of the present invention may be configured toprovide for elution of a therapeutic agent over a “short term” (i.e.,less than 30 days) and/or over a “long term” (i.e., more than 30 days).

Depending on the application, the most appropriate elution rate(s) maydepend upon a variety of factors, including one or more clinicalindication(s), the patient, the specific location within the body, andthe therapeutic composition to be delivered.

For example, a desired elution rate may comprise an initial burstdelivery followed by delivery of a lower dosage over a short term, whileanother desired rate may comprise an initial delivery of a firsttherapeutic composition and a follow-up delivery of a second therapeuticcomposition. Yet another desired rate may comprise intermittent deliveryover a long term and a reserve for later, controlled delivery by amedical practitioner. The present invention meets these needs.

Being able to manipulate elution rates, and to do so in a predictablemanner by structurally altering elution pathways as described herein,thus has significant implications. In this regard, exemplary embodimentsof the present invention further comprise methods for predicting elutionrates for therapeutic-releasing constructions and related methods fordesigning constructions to provide desired elution rates.

Elution rates may be predicted analytically, using computational fluiddynamics (“CFD”), and/or experimentally, each of which may be used tovalidate the others. CFD solves conservation equations to predict themovement, or flux, of chemical species within the fluid and acrossdefined boundaries.

In exemplary embodiments, predicting elution rates analytically maycomprise using one or more equations taking into account one or more ofthe factors including geometry, tortuosity, the diffusion length, thediffusion coefficient, and the void volume. Equation (1) is such anequation suitable for simple geometries.

$\begin{matrix}{\frac{M_{t}}{M_{\infty}} = {1 - {\sum\limits_{n = 0}^{\infty}{\frac{8}{( {{2\; n} + 1} )^{2}\pi^{2}}^{{- {D_{e}{({{2n} + 1})}}^{2}}\pi^{2}{t/4}\; \gamma^{2}}}}}} & (1)\end{matrix}$

Where τ is the tortuosity, γ is the diffusion length, D is the diffusioncoefficient, and the void volume is represented by ε in Equation (2)such that:

$\begin{matrix}{D_{e} = \frac{D\; ɛ}{\tau}} & (2)\end{matrix}$

Predicting elution rates in exemplary embodiments using CFD may comprisemodeling a construction geometry and meshing the model with anappropriate interval size of elements. An interval size may be fromabout 5×10⁻⁵ m to about 1×10⁻³ m, more preferably from about 4×10⁻⁴ m toabout 1×10⁻⁴ m, and most preferably about 4×10⁻⁴ m. Elements arepreferably quadrilateral (4-node), triangular (3-node), or a combinationthereof. Predicting elution rates in this manner may further compriseapplying appropriate boundary conditions and assigning materialproperties, which may include density, viscosity, molecular weight, andthe diffusion coefficient. In exemplary embodiments, some of theboundary conditions and material properties are kept constant as nothaving as much impact as other variables, for example, the geometry,tortuosity, the diffusion length, and the void volume.

Constructions may be designed by structurally altering elution pathwaysin ways believed (whether known or predicted analytically, using CFD,and/or experimentally) to provide desired elution rates. By way of anon-limiting example, and with reference now to FIG. 18, an exemplarymethod comprises a step 205 of identifying a therapeutic composition, astep 210 of identifying a desired elution rate, a step 215 of designinga therapeutic-releasing construction, and a step 220 of verifying thatthe therapeutic-releasing construction will deliver the therapeuticcomposition according to the desired elution rate.

The step of designing may comprise altering one or more of the proximityof the gaps between barriers to the opening, the size of the gapsbetween barriers, gaps between barrier ends and side walls, volumebetween barriers, constriction between barriers, staggering of barriers,orientation of barriers, and shape of barriers. In addition toalterations to pathway(s), designing may further comprise wrapping,stacking, gate(s), barrier mobility, opening(s), etc. The step ofverifying may be accomplished analytically, using CFD, and/orexperimentally, as described above.

An exemplary method may further comprise a step of re-designing atherapeutic-releasing construction if it can not be verified that thetherapeutic-releasing construction will deliver the therapeuticcomposition according to the desired elution rate.

EXAMPLES Example 1

A copolymer of tetrafluoroethylene/perfluoromethylvinylether (TFE/PMVE)as described in EP 1545642 B1 was obtained in a 0.12 wt % solution ofFluorinert FC-77 (3M, St Paul, Minn.). To this solution was added anappropriate amount of dexamethasone sodium phosphate (Spectrum, Gardena,Calif.) to produce a solution of 0.12 wt % of the drug. The solution wassonicated to ensure complete mixing.

An expanded polytetrafluoroethylene (ePTFE) film tape of approximately0.01 mm in thickness and 0.8 cm width was utilized in the manufacturingof the drug release system. A length of ePTFE film tape approximately 8cm long was mounted onto a flat sheet of aluminum foil with a section ofadhesive tape at each end. The ePTFE film tape was spray-coated with theTFE/PMVE and dexamethasone sodium phosphate solution using an airbrush(Badger standard set, model 350 (Badger Air Brush Co., Franklin Park,Ill.) set at 220 KPa gauge air pressure. Spray coating was conducted for2-3 minutes, the coating was allowed to air dry, and the coated filmthen coated again. This was continued until the coating mass added tothe tape was approximately 1 mg per 1 cm length. The opposite side ofthe film tape was left uncoated.

A metal tube of outside diameter of 1.50 mm, length 3 cm was obtained. Athin layer of a substantially non-porous composite film includingexpanded polytetrafluoroethylene (ePTFE) with a thermal adhesive layerof ethylene fluoroethylene perfluoride on one side was applied to thetube extending approximately 0.8 cm back from the tip of one end. Thisconstruction was utilized as a model cardiac pacing lead tip. The end ofa segment of the coated film tape of 0.8 cm width and 2 cm in length wasattached to the outer circumference of the tube, with the drug coatedside facing the tube, at its end utilizing a silicone adhesive (MED-137,NuSil Technology, Carpinteria Calif.) and allowed to fully cure. Aftercuring, a spatula was used to spread a thin film of the siliconeadhesive on the coated side of the coated tape, and the tape was wrappedwith the coated side toward the tube. The wrapped coated tape was thencapped on a portion of its outer surface using silicone applied with aspatula, while not coating a thin strip of approximately 1 mm or less inwidth adjacent to the opening of the coated tape wrapped metal tube. Theconstruction was allowed to cure overnight.

Constructions so made possessed a theoretical drug loading ofapproximately 2 mg and were tested for determination of drug release. Aconstruction was placed in a vial containing 3 ml of PBS and maintainedin a 37 degree C. incubator. Samples of 3 ml were taken at various timepoints and the vial replenished with fresh PBS to maintain the volume at3 ml. Drug concentration was measured on an UV spectrophotometer at 242nm. The graph shown in FIG. 4 demonstrates an extended elution time forthe drug dexamethasone sodium phosphate.

Example 2

In this example, analytical solutions for elution rates across the foursimple geometries shown in FIG. 19A were generated from Equation (1),according to methods described in Crank, J., 1975, The Mathematics ofDiffusion, Oxford University Press., which is hereby incorporated byreference in its entirety for all purposes. The analytical elution ratesare depicted in FIG. 19B.

Next, a CFD analysis was developed and used to generate solutions forelution rates across the same four simple geometries. The constructiongeometries were modeled in two dimensions (because of the assumptionthat the thickness of the model is significantly smaller than the x- ory-dimensions, which is well-supported with the validation presented) andthe models were meshed utilizing SolidWorks 2010 SP3.0 and Ansys 12.1. Atriangular (3-node) mesh was selected with an interval size of 4×10⁻⁴ m.Appropriate boundary conditions were applied and material propertieswere assigned. There was a zero diffusive flux across the walls, so thatdiffusion only occurred at the outlets of each geometry, the outletsbeing the left hand edges or faces of each geometric construct.Diffusion from each outlet is indicated by the arrows in FIG. 19A. Theconvective term at the outlet was also neglected. Initially the entiregeometry was assumed to be coated with the drug so that the there wereno voids, and the concentration of the drug at the outlet was zero. Thedensity, viscosity, and molecular weight for each species were set to 1and the diffusion coefficient was set to 1×10⁻⁶ cm²/s. The CFD elutionrates for the four simple geometries shown in FIG. 19A were generatedutilizing Fluent 12.1.4 and are depicted in FIG. 19C.

The CFD analysis was then validated against the analytical solutions bycomparison. The CFD solutions were compared to the data generated byEquation (1) and found to match within 3% of the series solution.

Finally, the validated CFD analysis was used to generate solutions forelution rates across the geometry of the construct in FIG. 20 and themore complex geometries of FIGS. 14A-14J. Note the construct in FIG. 20is a dimensioned version of that shown in FIGS. 8A and 8B noting thatthe thickness of the construction in FIG. 20 is modeled in twodimensions (because of the assumption that the thickness of the model issignificantly smaller than the x- or y-dimensions, which iswell-supported with the validation presented above). Irrespective of themodeled geometry, the boundary conditions, material properties and loadswere kept the same.

FIGS. 21A-21D depict percent elution versus days elapsed for theconstructions in FIGS. 14A-14J compared to the construction in FIG. 20.FIGS. 22A-22J depict therapeutic agent concentration at T=2.5 days forthe constructions in FIGS. 14A-14J. FIGS. 23A-23I depict therapeuticagent concentration at T=20 days for the constructions in FIGS. 14A-14I.

Example 3

In this example, the validated CFD analysis method described above wasused to generate solutions for comparative elution rates across theconstruction geometries shown in FIGS. 17A and 25A. The constructiongeometries were modeled in two dimensions (because of the assumptionthat the thickness of the model is significantly smaller than the x- ory-dimensions, which is well-supported with the validation presented) andthe models were meshed utilizing SolidWorks 2010 SP3.0 and Ansys 12.1. Atriangular (3-node) mesh was selected with an interval size of 4×10⁻⁴ m.Appropriate boundary conditions were applied and material propertieswere assigned. There was a zero diffusive flux across the walls, so thatdiffusion only occurred at the outlet. The convective term at the outletwas also neglected. Initially the entire geometry of the constructionsin FIGS. 17A and 25A was assumed to be coated with the drug so that thethere were no voids, and the concentration of the drug at the outlet waszero. The density, viscosity, and molecular weight for each species wereset to 1 and the diffusion coefficient was set to 4×10⁻⁶ cm²/s.Irrespective of the modeled geometry, the material properties and loadswere kept the same. The CFD analysis of the construction in FIG. 25Aassumed there was no gate affecting elution of the therapeutic agentsuch as gate (98) in FIG. 17A. For FIG. 17A, the gate (98) was initiallyassumed to represent a wall with zero diffusive flux. After one day (T=1day) had elapsed, the second application (the right side of FIG. 17A) ofthe therapeutic agent was allowed to release as the gate was assumed tohave dissolved (i.e., opened).

FIG. 25B is a plot depicting percent elution versus days elapsed for thegeometry with barriers (52) shown in FIG. 25A as compared to theconstruction without barriers in FIG. 20. As can be seen, the elutionprofile for the construction in FIG. 25A is slower then that for theconstruction shown in FIG. 20 due to the presence and locations ofbarriers (52).

FIG. 26 is a plot depicting comparative elution profiles over one day(T=1.0) between the left hand portion of the constructions shown in FIG.17A with gate (98) closed and the entire construction shown in FIG. 25Awhich has no such gate. The initial, shorter diffusion length of FIG.17A (the higher plot line) is evident as compared to that for theconstruct in FIG. 25A. Similar to the previously validated studies, whena shorter diffusion length is employed the rate of diffusion is faster.Since FIG. 17A has the gate closed the diffusion length is only half ofthe surface, whereas FIG. 25A is the entire surface, becoming a muchlarger diffusion length and thus slower rate of diffusion.

FIGS. 27A and 27B depict therapeutic agent concentrations at T=22.5hours for constructions shown in FIGS. 25A and 17A, respectively.Referring to FIG. 27A, it is apparent from the shading that the modeltherapeutic agent has begun to move from the volume on the right handside of the first barrier (52) (located in the middle of theconstruction) toward hole 42. Conversely, in FIG. 27B the volume of themodel drug to the right of the first barrier (52) is held in placebecause gate (98) in FIG. 17A has not opened.

FIGS. 24A-24C depict the fraction of therapeutic agent eluted versusdays elapsed for the constructions in FIGS. 14A-14I compared to theconstruction in FIG. 20. The longer term elution rates shown in FIGS.24A, 24B and 24C (versus those shown in FIGS. 21A-21C) demonstrate howthe rate of diffusion changes with time in the different embodiments.For example referring to FIG. 24A, prior to day 5, the configurationshown in FIG. 14C shows a faster rate of elution, whereas that for theconstruction in 14B is slower. However, beyond 5 days the rate for theconstruct in FIG. 14B surpasses that of the construction in FIG. 14C.This is shown again by comparing the elution rates for constructions inFIGS. 14I and 14H prior to day 5, against rates at around day 15 for thesame constructs shown in FIG. 24C. In each case this is related to theaccessibility of drug in the second (or third or fourth) partition(i.e., those areas between barriers (52)). Put another way, it is thegradual accumulation of diffusion length as each segment of theconstruct is accessed that causes this effect.

The therapeutic agent closest to the outlet naturally has a shorterdiffusion length (and faster rate of diffusion) whereas the drug that isfarthest from the outlet has the longest path and slowest rate ofdiffusion. As the drug on each subsection or partition between barriers(52) diffuses, a concentration gradient is created which initiatesdiffusion from the next section. As the drug on each subsequent sectiondiffuses, there is an accumulation of effective diffusion length. Thepoints at which the diffusion curves in FIGS. 24A-24C intersectrepresent the time when the effective diffusion lengths for eachrespective configurations are equal.

For example, the constructions shown in FIGS. 14A and 14C featurebarriers (52) the shape, size, and angles of which are identical andserve to create four reservoirs or partitioned areas (from left to rightin the drawings). The only difference between the constructions in FIGS.14A and 14C is the diffusion path length between opening (42) and thesecond partition. As shown in FIG. 24A, initially each construct hasvery similar diffusion rates because the initial path (i.e., from thefirst partition) is short. However, as shown in FIG. 14C the gap betweenbarrier (52) and side of the impermeable material (12) is closer to theoutlet and therefore there is a closer proximity to the secondpartition, and a second diffusion length. In the construction shown inFIG. 14A diffusion occurs from one direction (bottom towards top)whereas for the construction in FIG. 14C diffusion occurs in twodirections (bottom towards top and left to right). After about 7 days ofdiffusion the effect is evident as the rate of diffusion for FIG. 14Cbecomes greater than that for FIG. 14A as shown in the plot in FIG. 24A.Once the additional partitions in the constructs in FIGS. 14A and 14Care accessed the overall shorter diffusion length of the construct inFIG. 14C remains clear as the amount diffused from the construct in FIG.14A is consistently less than the amount diffused from the construct inFIG. 14C for any given point in time.

Similarly, the construct in FIG. 14B initially is drawing from adistance that is equivalent to the length (from left to right in theFigure) of the construct. Consequently, the theory shown in the plots inFIG. 19B applies, where a longer diffusion length equates to a slowerelution. However once the accumulated effective diffusion length of theconstruct in FIG. 14C becomes greater than that of the construct in FIG.14B, that is when enough partitions are involved in the diffusionprocess, the amount diffused from the construct in FIG. 14B becomesgreater than that diffused from the construct in FIG. 14C.

1. A therapeutic-releasing device comprising: a firsttherapeutic-releasing construction including: a first coated film; afirst therapeutic agent incorporated within the first coated film; afirst capping layer that substantially covers all of the first coatedfilm and is impermeable to the first therapeutic agent; and a firstopening in the first capping layer; and a second therapeutic-releasingconstruction including: a second coated film; a second therapeutic agentincorporated within the second coated film; a second capping layer thatsubstantially covers all of the second coated film and is impermeable tothe second therapeutic agent; and a second opening in the second cappinglayer, wherein the first therapeutic-releasing construction is stackedinside the second therapeutic-releasing construction.
 2. Thetherapeutic-releasing device of claim 1, wherein the firsttherapeutic-releasing construction further includes a first elutionpathway for the first therapeutic agent through the first coated filmthat exits the first coated film at the first opening.
 3. Thetherapeutic-releasing device of claim 2, wherein the secondtherapeutic-releasing construction further includes a second elutionpathway for the second therapeutic agent through the second coated filmthat exits the second coated film at the second opening.
 4. Thetherapeutic-releasing device of claim 3, wherein the first coated filmis a polymeric material comprising one or more polymeric barriers thatare substantially impermeable to the first therapeutic agent and definethe first elution pathway.
 5. The therapeutic-releasing device of claim4, wherein the second coated film is a polymeric material comprising oneor more polymeric barriers that are substantially impermeable to thesecond therapeutic agent and define the second elution pathway.
 6. Thetherapeutic-releasing device of claim 3, wherein the first opening andthe second opening expose the first coated film and the second coatedfilm, respectively, to an external environment.
 7. Thetherapeutic-releasing device of claim 6, wherein the first opening isaligned with the second opening.
 8. The therapeutic-releasing device ofclaim 6, wherein the first opening is offset from the second opening. 9.The therapeutic-releasing device of claim 1, wherein the firsttherapeutic agent has a first potency and the second therapeutic agenthas a second potency.
 10. The therapeutic-releasing device of claim 1,wherein the first therapeutic agent is the same as the secondtherapeutic agent.
 11. The therapeutic-releasing device of claim 1, thefirst coated film is expanded polytetrafluoroethylene impregnated with acopolymer into which has been admixed the first therapeutic agent, andthe second coated film is expanded polytetrafluoroethylene impregnatedwith the copolymer into which has been admixed the second therapeuticagent.
 12. The therapeutic-releasing device of claim 1, wherein thefirst capping layer is a silicone composition and the second cappinglayer is the silicone composition.
 13. The therapeutic-releasing deviceof claim 1, wherein the first therapeutic-releasing construction is in aform of a cylinder and the second therapeutic-releasing construction isin a form of a cylinder.
 14. The therapeutic-releasing device of claim13, wherein the first therapeutic-releasing construction is enclosed onboth ends of the cylinder and the second therapeutic-releasingconstruction is enclosed on both ends of the cylinder.
 15. Atherapeutic-releasing device comprising: a plurality oftherapeutic-releasing constructions stacked inside one another, whereineach of the therapeutic-releasing constructions includes: a coated film;a therapeutic agent incorporated within the coated film; a capping layerthat substantially covers all of the coated film and is impermeable tothe therapeutic agent; and an opening in the capping layer.
 16. Thetherapeutic-releasing device of claim 15, wherein each of thetherapeutic-releasing constructions further includes an elution pathwayfor the therapeutic agent through first coated film that exits thecoated film at the opening.
 17. The therapeutic-releasing device ofclaim 16, wherein the coated film is a polymeric material comprising oneor more polymeric barriers that are substantially impermeable to thetherapeutic agent and define the elution pathway.
 18. Thetherapeutic-releasing device of claim 17, the coated film is expandedpolytetrafluoroethylene impregnated with a copolymer into which has beenadmixed the therapeutic agent.
 19. The therapeutic-releasing device ofclaim 18, wherein each of the therapeutic-releasing constructions is ina form of a cylinder.
 20. A therapeutic-releasing device comprising: aplurality of therapeutic-releasing constructions stacked inside oneanother, wherein each of the therapeutic-releasing constructionsincludes: a coated film; a therapeutic agent incorporated within thecoated film; a capping layer that substantially covers an exteriorsurface of the coated film and is impermeable to the therapeutic agent;an opening in the capping layer; and a substrate that completely coversan interior surface of the coated film and is impermeable to thetherapeutic agent.